The present invention is directed to novel compounds, to a process for their preparation, their use and pharmaceutical compositions comprising the novel compounds. The novel compounds are useful in therapy, and in particular for the treatment of pain during labor.
Although a wide spectrum of narcotics are now available, only a few are used currently in obstetrics, including morphine, pethidine, fentanyl and sufentanil. These narcotics can cause a variety of side effects in the mother, including respiratory depression, and orthostatic hypotension. Furthermore, because of their, lipophilic character, these opiate analgesics are transferred rapidly across the placenta and often produce neonatal respiratory depression and changes in the neurobehavior of the child. While these side effects are particularly pronounced when lipophilic opiates are administered systemically, they are still of some concern with the delivery of classical narcotics by the spinal or epidural route which were introduced in 1979 and are now widely accepted for obstetric analgesia.
Opioid peptides and their analogs have a reduced ability to cross the placental barrier because of their polar character. A number of opioid peptide analogs with high selectivity for xcexc opioid receptors and xcexc agonist properties have been developed (for a review, see P. W. Schiller, in xe2x80x9cProgress in Medicinal Chemistryxe2x80x9d, Vol. 28 (G. P. Ellis and G. B. West, eds.), Elsevier, Amsterdam, The Netherlands, 1991, pp. 301-340). Among these, the dermorphin related tetrapeptide analog H-Tyr-D-Arg-Phe-Lys-NH2 (DALDA) is particularly polar (P. W. Schiller et al., J. Med. Chem. 32, 698-703 (1989)). DALDA is also disclosed and claimed in U.S. Pat. No. 5,312,899, granted May 17, 1994 to P. W. Schiller and now assigned to the Applicant of the present application. DALDA shows high xcexc receptor affinity and excellent xcexc receptor selectivity in the rat brain membrane binding assay as well as considerable xcexc agonist potency in the functional guinea pig ileum (GPI) bioassay. However, like morphine, DALDA did produce delayed respiratory depression (2 h after i.th. administration) at a dose of 7.5 xcexcg (32xc3x97ED50).
The problem underlying the present invention was thus to provide novel compounds with improved xcexc agonist potency, as well as with as few side-effects as possible. More particularly the object of the invention was to improve the potency as well as the side-effect profile for compounds used particularly within the obstetrics field.
The present invention is directed to novel analogs of DALDA, defined by the formula I 
wherein
R1 is selected from
(i) linear or branched C1-C6 alkyl;
(ii) C1-C6 alkoxy;
R2 is selected from
(i) hydrogen;
(ii) linear or branched C1-C6 alkyl;
(iii) C1-C6 alkoxy;
R3 and R4 is each and independently selected from
(i) hydrogen;
(ii) linear or branched C1-C6 alkyl; 
R5, R6, R7, R8 and R9 is each and independently selected from
(i) hydrogen;
(ii) halogen, where xe2x80x9chalogenxe2x80x9d encompasses chloro, fluoro, bromo and iodo; and
(iii) linear or branched C1-C6 alkyl; and
n is an integer of from 1 to 5.
In a preferred embodiment of the present invention
R1 is a linear C1-C6 alkyl;
R2 is a linear C1-C6 alkyl or hydrogen;
R3 and R4 is each and independently selected from a straight C1-C6 alkyl or hydrogen;
R5, R6, R7, R8 and R9 is each and independently selected from
(i) hydrogen;
(ii) halogen, where xe2x80x9chalogenxe2x80x9d encompasses chloro, fluoro, bromo and iodo;
(iii) linear or branched C1-C6 alkyl; and
n is an integer of from 1 to 5.
In a particularly preferred embodiment of the present invention
R1 is CH3;
R2 is hydrogen or CH3;
R3 and R4 are both hydrogen; and
R5, R6, R7, R8 and R9 are all hydrogen; and
n is 4.
Within the scope of the invention are also pharmaceutically acceptable salts of the compounds of the formula I.
Suitable pharmaceutically acceptable salts of the compounds of formula I are the hydrochloride salt, the acetate salt and the trifluoroacetate salt.
The novel compounds of the present invention, which compounds are DALDA analogs, are useful in therapy, especially as analgesics, and particularly as analgesics within the field of obstetrics. The wording xe2x80x9canalgesicsxe2x80x9d is defined as absence of pain in response to stimulation which would normally be painful.
Also within the scope of the invention is the use of a compound of the formula I above, for the manufacture of a medicament for use as an analgesic, particularly as an analgesic within the field of obstetrics, more particularly for use in the treatment of pain during labor.
A further aspect of the invention is a method for the treatment of a subject suffering from pain, particularly pain during labor, whereby an effective amount of a compound of the formula I above, is administered to a patient in need of pain relief.
The compounds of the present invention may be prepared as described in the following.
Most Boc-amino acid derivatives used in the peptide syntheses are commercially available (Bachem Bioscience and RSP Amino Acid Analogues). 2-methyl-L-tyrosine (Mmt) was prepared by hydrogenolysis of 7-hydroxytetrahydroisoquinoline-3-carboxylic acid using Pd/H2 as described by P. Majer et al., Int. J. Peptide Protein Res. 43, 62-68 (1994).
All peptides were prepared by solid-phase techniques. The p-methylbenzhydrylamine resin was used for the solid-phase synthesis of the peptides which all contain a C-terminal carboxamide group. Boc protection of the amino group was employed in the preparation of all peptides. The syntheses were performed according to protocols that have been extensively used in the inventor""s laboratory (P. W. Schiller et al. J. Med. Chem. 36. 3182-3187 (1993)). Couplings were performed in a mixture of CH2Cl2/DMF (95:5; v/v), using 1,3-diisopropylcarbodiimide (DIC)/1-hydroxybenzotriazole (HOBt) as coupling agents. Completeness of coupling was carefully examined after each coupling step by means of the ninhydrin color test. The fully assembled peptide was cleaved from the resin and completely deprotected by treatment with liquid HF at 0xc2x0 C. and in the presence of anisole as scavenger (60-90 min).
The HPLC system GOLD (Beckman) consisting of the programmable solvent module 126 and the diode array detector module 168 was used in the purification and the purity control of the peptides. Reversed-phase HPLC was performed using a gradient made from two solvents: (A) 0.1% TFA in water and (B) 0.1% TFA in acetonitrile. For preparative runs a Vidac 218TP1022 column (250xc3x9722 mm) was used with a linear gradient of 5-20% B over a period of 30 min at a flow rate of 7 mil/min, absorptions being measured at both 216 nm and 280 nm. The same gradient was used for analytical runs on a Vidac 218TP0046 column (250xc3x974.6 mm) over a period of 30 min at a flow rate of 1.0 ml/min. Purity of peptides was also established by TLC on precoated silica gel plates 60F-254 (E. Merck, Darmstadt, Germany) in the following solvent systems (all v/v): (A) n-BuOH/AcOH/H2O (4:1:5, organic phase) and (B) n-BuOH/pyridine/AcOH/H2O (15:10:3;12). Peptides were visualized with UV and with the ninhydrin spray reagent. Molecular weights of peptides were determined by FAB mass spectrometry on an MS-50 HMTCTA mass spectrometer interfaced with a DS-90 data system.